Radiotherapy is one of the major therapeutic strategies for human
non-small cell lung cancer (NSCLC), but intrinsic radioresistance of
cancer cells makes a further improvement of
radiotherapy for NSCLC challenging. Mitochondrial function is frequently dysregulated in
cancer cells for adaptation to the changes of tumor microenvironment after exposure to radiation. Therefore, targeting mitochondrial biogenesis and bioenergetics is an attractive strategy to sensitize
cancer cells to
radiation therapy. In this study, we found that downregulation of single-strand
DNA-binding protein 1 (SSBP1) in H1299 cells was associated with inducing
mitochondrial dysfunction and increasing radiosensitivity to ionizing radiation. Mechanistically, SSBP1 loss induced
mitochondrial dysfunction via decreasing
mitochondrial DNA copy number and
ATP generation, enhancing the mitochondrial-derived ROS accumulation and downregulating key glycolytic
enzymes expression. SSBP1 knockdown increased the radiosensitivity of H1299 cells by inducing increased apoptosis, prolonged G2/M phase arrest and defective homologous recombination repair of DNA double-strand breaks. Our findings identified SSBP1 as a radioresistance-related
protein, providing potential novel mitochondrial target for sensitizing NSCLC to
radiotherapy.